Following a primary infection, Herpes simplex virus type 1 (HSV-1) invades sensory neurons of the trigeminal ganglion (TG), where it establishes a life-long latent (quiescent) infection. During latency no virus is produced and viral gene expression is largely repressed. In some humans periodic reactivation from the latent state results in HSV-1 release at the nerve termini, leading to potentially blinding herpes keratitis tha is characterized by inflammation, scarring, and progressive loss of vision. Devising methods to keep the virus in a latent state will provide crucial intervention in this blinding process. Work supported by this grant has contributed to a paradigm shift in understanding of HSV-1 latency from what was once considered a silent infection that is ignored by the host immune system to what is now believed to be a more dynamic infection in which viral gene expression in some neurons triggers CD8+ T lymphocytes to inhibit reactivation. While a role for CD8+ T cells in controlling HSV-1 latency is gaining wider acceptance, the involvement of CD4+ T cells that are also retained in latently infected TG has been largely ignored. The goals of the current application are to: Aim 1) Define the role of CD4+ and TCR- ?/?+ T cells in directly or indirectly inhibiting HSV-1 reactivation. Explore novel approaches to enhance the number of functional TG-resident T cells by: Aim 2 altering the microenvironment of the latently infected TG to make it more accessible to circulating HSV-specific T cells; and Aim 3) increasing the proliferation and function of TG-resident T cells by blocking the inhibitory receptors they express and eliminating inhibitory cytokines in the TG. While antiviral drugs appear to be useful for reducing the rate of recurrence of herpetic disease, we believe arming the immune system for the task is a superior approach in that it does not require life-long compliance with a drug treatment regimen, eliminates possible side-effects of long term drug use, and does not create the potential for drug resistant viral mutants. Therefore, we believe the treatment strategies developed in this proposal could greatly reduce the rate of recurrence herpetic eye disease and its blinding consequences.